Targeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis

Abstract

Lung cancer often has a poor prognosis, with brain metastases a major reason for mortality. We modified lonidamine (LND), an antiglycolytic drug with limited efficacy, to mitochondria-targeted mito-lonidamine (Mito-LND) which is 100-fold more potent. Mito-LND, a tumor-selective inhibitor of oxidative phosphorylation, inhibits mitochondrial bioenergetics in lung cancer cells and mitigates lung cancer cell viability, growth, progression, and metastasis of lung cancer xenografts in mice. Mito-LND blocks lung tumor development and brain metastasis by inhibiting mitochondrial bioenergetics, stimulating the formation of reactive oxygen species, oxidizing mitochondrial peroxiredoxin, inactivating AKT/mTOR/p70S6K signaling, and inducing autophagic cell death in lung cancer cells. Mito-LND causes no toxicity in mice even when administered for eight weeks at 50 times the effective cancer inhibitory dose. Collectively, these findings show that mitochondrial targeting of LND is a promising therapeutic approach for investigating the role of autophagy in mitigating lung cancer development and brain metastasis.

Complex Mitochondrial Dysfunction Induced by TPP+-Gentisic Acid and Mitochondrial Translation Inhibition by Doxycycline Evokes Synergistic Lethality in Breast Cancer Cells

“…Several studies have reported drug delivery systems for the transport of anticancer compounds to the mitochondria [18], highlighting the use of the lipophilic cations pyridinium [53][54][55] and TPP + [56][57][58][59]. In particular, we showed that TPP + derivatives of gallic acid and GA selectively induce cell death in BC cells [19,20] in a receptor status-independent manner [20] without toxic effects on nontumoral tissues in vivo [21].…”

Natural Agents Targeting Mitochondria in Cancer

“…These mitocans failed to prove themselves in terms of sensitivity and efficacy in the latter stage of clinical trials. On the other side, Mito-LND and NSC13062 are the compounds that have the preliminary evidence of affecting the mitochondria of cancer cells and are proposed as possible mitocans [ 112 , 113 , 114 , 115 , 116 ]. Table 1 a,b enlist some widely studied synthetic mitocans, their class, and associated studies.…”

Targeting the Redox Landscape in Cancer Therapy

“…Notably, the anticancer drug lonidamine (LND) has been reported to inhibit complex II, and to increase the overall treatment response in cancer patients in combination with standard-of-care drugs, e.g., doxorubicin [35,36]. However, LND showed limited efficiency in clinical phase 3 trials but was recently modified into mito-lonidamine (Mito-LND), which is 100-fold more potent in cell culture and mouse models, and inhibits complex I and II [31].…”